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  • Agitation is a subtype of delirium, characterized by an excess of behaviors including aggression, akathisia, disinhibition, and emotional lability.1
  • Aggression, a complex behavior comprised of sensory, emotional, cognitive, and motor elements, can include behaviors that are damaging to individuals or property; attitudes, moods, or gestures that people find threatening or intimidating; or purposeful behavior that is disruptive to social integration.1
  • Apathy, generally speaking, is a decrease in or lack of motivation.2 It is also described as a decrease in self-generated, voluntary, and purposeful behaviors.3


  • Agitation and aggression can occur within the context of any condition that acutely affects the brain. Such conditions include: traumatic brain injury (TBI), non-traumatic brain injury (including ischemic and thrombotic stroke), anoxia, neuro-degenerative disorders, neoplastic disorders, central nervous system infection, and toxic or metabolic encephalopathy.
  • Apathy is seen in multiple psychiatric conditions (including depression and schizophrenia) as well as neurologic disorders (such as Alzheimer’s and other types of dementia), in addition to Parkinson’s Disease, stroke, traumatic brain injury, cerebral infections, and tumors.
  • Secondary conditions that commonly occur with TBI and stroke can present as agitation, aggression, or apathy. For example, a severe aphasia often leads to behavioral deficits as the individual is frustrated with the inability to communicate.

Epidemiology including risk factors and primary prevention

  • The incidence and prevalence of agitation are dependent on the underlying etiology. In severe TBI, the incidence of agitation among patients in acute rehabilitation has been estimated to be at least 40%.4 Patients are more likely to have agitation after head injury if they are still in the state of post-traumatic amnesia, if their injury was more severe, if they have a premorbid history of substance abuse,4,5 infection, impaired cognition or lower functional status.6Agitation has been noted in 20 to 45% of patients with mild cognitive impairment and up to 90% of patients with advanced dementia.7
  • Estimates about the epidemiology of aggression also vary with underlying cause. Among patients with severe TBI, the prevalence of aggression is at least 30%.8 Patients are more likely to have aggression after TBI if they have a pre-injury history of mood disorder, alcohol or substance abuse, frontal lobe lesion, prior episodes of head injuries or history of arrest.9 Other risk factors for aggression include the presence of delirium, low cognitive status, comorbid medical complications, and poor language function.4,9 In dementia, the prevalence of aggression has been estimated to range from 20 to 50%. The development of aggression in dementia has been correlated with disease severity, depression and degree of cognitive impairment.7
  • The incidence of apathy varies with the etiology. For example, it occurs in about 36% of post-stroke patients10 and up to 90% in patients who have Alzheimer’s disease.11 In the TBI population, apathy has been present in 20-70% of studied patients, with the average prevalence of 48%.12


  • The pathology underlying agitation and aggression is not fully understood and is likely multifactorial. Cerebral structural and chemical abnormalities that have been implicated include: damage to the frontal and temporal lobes, injury to the prefrontal cortex, injury to the thalamus and limbic system, and impaired regulation of serotonin, norepinephrine, and dopamine.4,7,13
  • Apathy has been associated with damage to multiple areas of the brain, including the frontal lobe, basal ganglia, and cingulate gyrus. Blockade of dopamine pathways also appear to play a role.14

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

  • Agitation following TBI tends to resolve when the delirium resolves. In neurodegenerative disorders, including dementia, agitation may be an ongoing problem.
  • Aggression following TBI can either resolve when the agitation resolves or remain an ongoing problem. In neurodegenerative disorders, including dementia, it may also be an ongoing problem.
  • Apathy may improve if the underlying condition heals or is adequately treated.

Specific secondary or associated conditions and complications

Agitation and aggression can have dramatically deleterious sequelae for patients with TBI and other acquired brain injuries. Agitation and aggression have been associated with interruptions and disruptions of care. These behavioral changes have also been correlated with increased lengths of stay in both hospital and acute rehabilitation settings.  The overall cost of care can be increased. There is also a high potential for injury to the patient or others. The burden on caregivers can be more intense when a patient is agitated or aggressive. Agitation and aggression can also lead to significant social issues, including alienation from family and loss of employment. Further, there can be difficult legal issues, which can be exaggerated if the patient engages in criminal activity.1,4,13,15



For patients with agitation and aggression, a detailed history should include the history of the inciting injury or disease, social history (including education, employment), medical history (including neurological, psychiatric and endocrine systems), sleep history, nutritional status, and pain assessment. History of substance abuse, including drugs, tobacco, and alcohol use, are important as withdrawal, craving, and other sequela of use could contribute to the patient’s agitation and aggression.

For patients with apathy, the history should include past medical history (including history of psychiatric illness), personality changes, and progression of disease. To rule out a potentially treatable cause of apathy, screening for depression should be done early.

Physical examination

For agitation and aggression, the physical exam should include vital signs (may be abnormal in cases of infection or medical instability), neurological examination (could provide focal findings or clues to the underlying pathology), cardiovascular and pulmonary evaluations (acute medical issues), and musculoskeletal examination (potential sources of discomfort or pain). Assessment for aphasia, hallucinations, memory deficits, and other issues may yield clues about agitation and aggression. Ranchos Los Amigos scale may be helpful in assessing patients with TBI and for communicating their status with other team members.

Functional assessment

Patients with agitation and aggression require careful functional assessments. Agitation and aggression are associated with abnormalities in executive function, impulse regulation, and impaired ability to perform basic self-care tasks. Further, the behaviors associated with agitation and aggression can interfere with caregiving activities in patients who would benefit from assistance.9 The negative effect on ability to function can be profound.

For apathy, the patient’s affect as well as what they do from a functional standpoint should be assessed. It is important to differentiate whether patients are not doing activities of daily living (ADLs)/self-care because they are not motivated, or not being able to remember to do those tasks due to cognitive impairment or lack of insight.

Laboratory studies

For agitation and aggression, the basic laboratory work-up would start with chemistry and complete blood count to evaluate for common metabolic or hematologic abnormalities. Other tests may be required to evaluate for specific metabolic problems and infectious issues. Cerebrospinal fluid analysis may be warranted, particularly if the underlying cause of the agitation or aggression is thought to be infectious, inflammatory, or related to a paraneoplastic syndrome.


For patients with agitation and aggression, brain imaging such as CT or MRI would be needed to ascertain an underlying etiology if it were not already known. If the agitation or aggression is possibly due to pain, x-rays can evaluate for previously undiagnosed fractures or heterotopic ossification.

Supplemental assessment tools

  • Agitation: For patients with TBI, the Agitated Behavior Scale can help clinicians quantify the agitated behaviors at a certain point in time and over a period of time.16 For patients with dementia, the Behavioral Pathology in Alzheimer’s Disease Rating Scale may be helpful.7
  • Aggression: Two commonly used tools are the Neurobehavioral Functioning Inventory (NFI) and the Neurobehavioral Rating Scale.9
  • Apathy: There are multiple available assessment tools, including the Apathy Evaluation Scale, the Apathy Scale, and the Apathy Inventory. Furthermore, the Neuropsychiatric Inventory and the Unified Parkinson’s Disease Rating Scale both assess apathy as part of their overall measure.3,11
  • Frontal seizures can be mistaken as behavioral issues. In some cases, an electroencephalogram (EEG) may, therefore, be indicated.


Agitation and aggression can be impacted both positively and negatively by environmental issues. These include the amount of stimulation, light and noise levels, space and privacy issues, and interactions with staff members, other patients, and family/friends.15,17 Environmental interventions can be helpful in management


At different disease stages

  • For agitation and aggression, interventions should first include modifying the environment (reduction of stimuli including televisions and phones, visitors, other patients, and medical equipment), normalizing the sleep-wake cycles, optimizing nutrition, and avoiding physical restraints.17 If further intervention is needed, medications that may be helpful include benzodiazepines, anticonvulsants, antidepressants, antipsychotics, buspirone, amantadine, beta-blockers, and lithium. However, in acute brain-injured patients, it is recommended that benzodiazepines and typical antipsychotics be avoided if possible, as they may inhibit cognitive recovery.18,19,20
  • For apathy, there are no FDA-approved medication treatments. Some small studies and case reports have demonstrated possible beneficial effects of certain medications. These include anti-cholinesterase inhibitors such as rivastigmine, donepezil, and galantamine and psychostimulants such as methylphenidate, modafinil and armodafinil. Antidepressants, especially more activating ones, are also used in this population.3

Coordination of care

The interdisciplinary treatment team includes the physician, nurse, occupational therapist, physical therapist, recreation therapist, speech and language pathologist, neuropsychologist and others. Care can be provided in a variety of settings, including inpatient rehabilitation units, outpatient therapies, structured day programs, residential treatment, inpatient pychiatric treatment, and in-home cognitive services.20

Patient & family education

In cases of acute brain injury, where the agitation or aggression may be transient and is consistent with stages of recovery, family members need education about the situation. Visitors are also part of the therapeutic environment, so their visits may need to be shortened or scheduled around rest periods for the patient. Families should have knowledge of potential situations that trigger agitated or aggressive behaviors so these can be avoided.9 In cases of neurodegenerative injury, including dementia, families need education about the expected prognosis and time course. They may need assistance setting up ongoing care for the patient.7


Cutting edge concepts and practice

For agitation and aggression, there have been reports of the successful use of electroconvulsive therapy. Complementary and alternative therapy modalities, including massage therapy and essential oils, have also been implemented.16 However, these trials have not been large or generalizable enough to be widely applied. Additional research is needed.


Gaps in the evidence-based knowledge

For aggression and agitation following traumatic and acquired brain injury, there are many unsettled questions for rehabilitation clinicians and investigators to consider. It is possible that future therapies could shorten the length of the agitated and aggressive period of recovery, thereby lessening the burden of these conditions. This clinical area would benefit from studies utilizing consistent nosology and methodology to facilitate generalizability.9,20


  1. Sandel E, Mysiw WJ. The agitated brain injured patient. Part 1: Definitions, differential diagnosis, and assessment. Arch Phys Med Rehabil. 1996;77:617-623.
  2. Marin RS, Wilkosz PA. Disorders of diminished motivation. In: Silver JM, McAllister TW, Yudofsky SC, eds. Textbook of Traumatic Brain Injury, 2nd Ed. 2011. Washington, DC: American Psychiatric Publishing Inc.
  3. Levy R & Dubois B. Apathy and the functional anatomy of yje prefrontal cortex-basal ganglia circuits. Cerebral Cortex. 2006; 16(7): 916-928
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  16. Corrigan JD. Development of a scale for assessment of agitation following traumatic brain injury. J Clin Exp Neuropsychol. 1989;11:261-267.
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  18. Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury: A state of the art review. J Rehabil Res Dev. 2009;46:851-879.
  19. Fleminger S, Greenwood RRJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane review 2008. Wiley.
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Original Version of the Topic:

Joseph A. Rosenthal, MD. Agitation/aggression/apathy after brain injury and other CNS disorders. Publication Date: 2013/09/20.

Author Disclosure

Joseph A. Rosenthal, MD
Research grant from NIDRR as an investigator for Ohio Valley Regional TBI Model Systems.

Diane Mortimer, MD
Nothing to Disclose